The present invention relates to a pharmaceutical formulation of nasal administration containing a pharmaceutically active polypeptide, and particularly relates to a pharmaceutical formulation for nasal administration that comprises at least one compound selected from the group consisting of taurine, an ester thereof with C18 6 alcohol, a base metal salt of taurine, hyaluronic acid and a base metal salt of hyaluronic acid. These compounds are used as absorbefacients for the pharmaceutical formulation of the present invention. The pharmaceutical formulation of the present invention may be dosed through nasal mucosa. The present invention also relates to a method for producing the pharmaceutical formulation.
A powder composition for nasal administration including a physiologically active peptide with a hyaluronic acid butyrene glycol ester as a carrier is disclosed in Japanese Patent Publication (laid-open) No. 6-199681. A pharmaceutical composition for administration through nasal mucosa, with preferably a pH of about 4, containing a peptide hormone and hyaluronic acid or its salt is disclosed in Japanese Patent Publication (laid-open) No. 3-246233. A microsphere formed comprising a physiologically active peptide that is surrounded by hyaluronic acid esters or which is adsorbed on hyaluronic acid esters is disclosed in Japanese Patent Publication (laid-open) No. 7-179363. A pharmaceutical formulation with improved drug delivery comprising a physiologically active peptide, hyaluronic acid or a non-toxic salt of these compounds, and polymer substance is disclosed in Japanese Patent Publication (laid-open) No. 5-97694. A pharmaceutical formulation for administration through the lung that comprises peptide type drugs and hyaluronic acid is disclosed in Japanese Patent Publication (laid-open) No. 9-309843. A pharmaceutical formulation with sustained physiological activity comprising hyaluronic acid or its non-toxic salts is disclosed in Japanese Patent Publication (laid-open) No. 2-213. A powder pharmaceutical formulation for nasal administration that contains a granulocyte colony stimulating factor, saccharides, hyaluronic acid or its salt is disclosed in Japanese Patent Publication (laid-open) No. 8-198772. An eye drop containing insulin and hyaluronic acid or its salt as a thickening agent is disclosed in Japanese Patent Publication (laid-open) No.1-294633. An aqueous pharmaceutical composition with sustained pharmaceutical activity that contains a pharmaceutically active peptide, water soluble hyaluronic acid, and a water soluble protein which does not exhibit pharmaceutical activity is disclosed in Japanese Patent Publication (laid-open) No. 5-186362. A peptide composition having a physiologically active peptide homogenously dispersed in a carrier hyaluronic acid so that it is adhesively bound to the carrier is disclosed in Japanese Patent Publication (laid-open) No. 7-118170. A super-absorbent drug for administration through vagina that contains the absorbefacient taurine in a bioactive polypeptide is disclosed in Japanese Patent Publication (laid-open) No. 3-99021. In Chinese Patent Application No. 95119260.4, an absorbefacient for absorption of peptide containing pharmaceuticals through mucosae is disclosed. The absorbefacients disclosed in the above Chinese application include azone, saponins, glycyrrhizionic acid, and esters, salts of these compounds, glycyrrhetinic acid and a sodium salt of glycyrrhetinic acid, dihydroxymorintannic acid and its derivatives, and carboxylic acid estes of these compounds. However, the only formulation example disclosed in the above Chinese Patent Application is a sublingual tablet containing such absorbefacients. In Chinese Patent Application No. 88106763.6, a pharmaceutical formulation for administration through mucosae is disclosed. The absorbefacients contained in the formulation are monosaccarides such as D-erythrose, D-ribose, D-ribulose, D-xylose, D-arabinose, D-mannose, L-sorbose, D-sedumtheptulose, or monosacarides such as xcex1-cyclodextrin, xcex2-cyclodextrin, xcex3-cyclodextrin, and cyclodextrin having side chains.
Polypeptide compounds are easily degraded with enzymes in the human stomach and intestines and are easily metabolized in the human liver. Therefore, polypeptide compounds are difficult to give their intrinsic pharmaceutical effects in a patient""s body. Thus, polypeptide compounds are generally administration as various injections such as hypodermic injections, intramuscular injections, and intravenous injections. However, the patient experiences pain and irritation such as, for example, injury and necrosis of his/her muscle tissue during long-term polypeptide administration of the injections and there is potential for infections caused by injection due to communicable diseases. The patient also experiences various inconveniences such as the need to receive regular outpatient treatment. For these reasons, extensive studies have recently been made to administer the polypeptide compounds through mucosae such as the nasal mucosa, no polypeptide containing pharmaceutical formulations for administration through the nasal mucosa have not yet been commercially available.
Therefore, polypeptide containing pharmaceutical formulations for administration through nasal mucosa are highly desired and their development has been waited for a long term.
An object of the present invention is to provided a pharmaceutical formulation for nasal administration containing a pharmaceutically active polypeptide and also to provide a method for producing thereof.
The inventor has found a novel pharmaceutical formulation suitable for nasal administration and succeeded in accomplishing the present invention as the result of the study to solve the above problems. The novel pharmaceutical formulation containing a pharmaceutically active polypeptide exhibits high pharmaceutical activity as high as the pharmaceutical activity obtained in the administration through injection and does not irritate patients.
According to the present invention, the pharmaceutical formulation for nasal administration comprises (1) a pharmaceutically active polypeptide, (2) at least one compound selected from the group consisting of taurine, an ester thereof with C1xcx9c6 alcohol, an base metal salt of taurine, hyaluronic acid and a base metal salt of hyaluronic acid, and (3) at least one pharmacologically acceptable additive.
Further according to the present invention, the pharmaceutical formulation for nasal administration preferably comprises (1) a pharmaceutically active polypeptide, (2) at least one compound selected from the group consisting of taurine, an ester thereof with C1xcx9c6 alcohol, a base metal salt of taurine, (3) at least one compound selected from hyaluronic acid and a base metal salt of hyaluronic acid, and (4) at least one pharmacologically acceptable additive.
Further according to the present invention, the pharmaceutical formulation for nasal administration more preferably comprises (1) a pharmaceutically active polypeptide, (2) taurine and hyaluronic acid, and (3) at least one pharmacologically acceptable additive.
Further according to the present invention, the pharmaceutical formulation may comprise at least one compound selected from the group consisting of taurine, an ester thereof with C1xcx9c6 alcohol, a base metal salt of taurine, hyaluronic acid, a base metal salt of hyaluronic acid and a mixture thereof or a carrier for the pharmaceutically active polypeptide for administration through the nasal mucosa.
In accordance with the present invention, a method for producing a pharmacological formulation is also provided. The method for producing a pharmaceutical formulation for nasal administration containing of at least one pharmaceutically active polypeptide comprises the steps of;
adding an adequate amount of distilled water to a compound selected from the group consisting of taurine, an ester thereof with C1xcx9c6 alcohol, a base metal salt of taurine, hyaluronic acid, a base metal salt of the hyaluronic acid, a mixture thereof, and an optional additive to form a solution of the ingredients;
adjusting the pH of the solution formed by dissolving the compounds; and
adding a pharmaceutically active polypeptide to the solution and dissolving the pharmaceutically active polypeptide.
Further according to the present invention, the method for producing the pharmaceutical formulation may further include the steps of:
filtering the solution for sterilization thereof; and
filling a bottle with the filtrate.
In the present invention, examples of the pharmaceutically active polypeptide include natural insulin obtained from cow and pig or synthetic insulin, calcitonin, hirudin, glucagon, angiotensin, lactation hormone, growth hormone, thyroid-stimulating hormone (THS) or thyrotropin, adrenocorticotropin, and interferon, and mixtures thereof.
In a preferred embodiment of the present invention, a pharmaceutical formulation to be administered through the nasal mucosa for treatment of diabetes is provided. The pharmaceutical formulation of the preferred embodiment contains insulin as the above pharmaceutically active polypeptide.
The base metal salt of taurine is used as one of the absorbefacients which is contained in the pharmaceutical formulation for nasal administration according to the present invention. Exemplary base metal salts may include sodium salts of taurine and potassium salts of taurine, and the like. The base metal salt of hyaluronic acid is used as one of the absorbefacients which is contained in the pharmaceutical formulation for nasal administration according to the present invention. Exemplary of base metal salts may include sodium salts of hyaluronic acid and potassium salts of hyaluronic acid, and the like.
Insulin is one of the effective ingredients of the pharmaceutical formulation for nasal administration of the present invention and examples may include natural insulin obtained from cow and pig, synthetic insulin and insulin produced by a recombinant DNA technique.
Diabetes which is to be treated with the insulin-containing pharmaceutical formulation for nasal administration of the present invention may be type I diabetes or type II diabetes.
The pharmaceutical formulation for nasal administration of the present invention may be preferably formulated as a liquid drop type drug or a spray type drug. The pharmaceutical formulation for nasal administration of the present invention which may be provided either as a liquid drop type drug or as a spray type drug may be dosed, for example, through the nasal mucosa to a human.
The pharmaceutically active polypeptide containing pharmaceutical formulation of the present invention may possibly formulated from the pharmaceutically active polypeptide together with an absorbefacient and/or a carrier. However, the inventor has found that significant therapeutic effect is obtained when the pharmaceutical formulation for nasal administration includes simultaneously the pharmaceutically active polypeptide, absorbefacient taurine or a derivative thereof and carrier hyaluronic acid or a derivative thereof.
The pharmaceutically active polypeptide containing pharmaceutical formulation for nasal administration of the present invention may preferably contain 0.01xcx9c20 w/v % of at least one absorbefacient compound selected from taurine, its ester with C1xcx9c6 alcohol, and its base metal salt and at least one carrier compound selected from 0.01xcx9c10 w/v % of at least one compound selected from hyaluronic acid and its base metal salts, or a mixture thereof.
In the present invention, an aqueous solution containing a pharmaceutically active polypeptide or a pharmaceutical formulation for nasal administration, the pH may generally range from 6 to 8, more preferably range from 6.5 to 7.5.
The pharmaceutical formulation for nasal administration of the present invention which contains a pharmaceutically active polypeptide may be produced, for example, according to the following steps;
adding an adequate amount of distilled water to a compound selected from the group consisting of taurine, its ester with C1xcx9c6 alcohol, its base metal salt, hyaluronic acid, its base metal salt of the hyaluronic acid, a mixture thereof, and an optional additive such as, for example, a preserving agent Nipagin A (p-hydroxybenzoic acid ethyl ester) to form a solution of the ingredients;
adjusting the pH of the solution to between 6.5 and 7.5, more preferably to about 7.0, with 0.1 N HCl or 0.1N NaOH after dissolving the compounds by heating the mixture; and
adding a pharmaceutically active polypeptide such as insulin to the above solution and dissolving the pharmaceutically active polypeptide.
The above process may optionally includes the steps of:
filtering the above solution for sterilization thereof; and
filling a bottle with the filtrate. The bottle may be specially produced for this purpose.
According to the present invention, the dose of the pharmaceutically active polypeptide containing pharmaceutical formulation for administration through the nasal mucosa may vary with patient""s age, body weight, health condition, the severity of the disease, drugs to be simultaneously administered, their kinds, and the kinds of the pharmaceutically active polypeptides. Generally, the dose of the pharmaceutical formulation for nasal administration of the present invention which contains a pharmaceutically active polypeptide may be determined according to known doses of the pharmaceutically active polypeptide used.